ABSTRACT This application attempts to clarify the mechanistic basis for the association between excessive adiposity and risk factors for prostate cancer-specific morbidity and mortality in men with clinically localized prostate cancer. The overall hypothesis is that excess adiposity alters prostatic exposure to nutritional, hormonal, and immunologic factors influenced by weight status and implicated in prostate cancer progression, and that inter- individual variation in gland-level exposure to these factors mediates the effects of adiposity on the pathologic presentation and course of the disease. To test this hypothesis, we will: Aim 1) conduct a prospective 2-year cohort study of incident cases of clinically localized prostate cancer to measure the association of adiposity with pathologic tumor features at diagnosis and 2-year risk of biochemical (PSA) failure after radical prostatectomy; Aim 2) measure fatty acids, insulin-like growth factor (IGF) axis activity, modulators of inflammation, and sex steroid hormone profiles in prostate tissue and periprostatic fat collected at surgery, and use mediation model analysis to determine which physiologic variables account for the effects adiposity on tumor characteristics and risk of biochemical failure; Aim 3) and evaluate the effects of post-treatment changes in adiposity on 2-year risk of biochemical failure. The cohort will consist of 540 men enrolled in the urology clinics of four Chicago-area medical centers who are awaiting prostatectomy for clinically localized prostate cancer. Adiposity will be quantified by anthropometry and dual energy x-ray absorptiometry at diagnosis and one year after surgery. Pathologic tumor characteristics will be determined by a single pathologist, and biochemical outcomes will be ascertained using a standard clinical protocol. Potential mediators to be studied include fatty acids, the IGF-1 receptor signaling pathway, adipose tissue-derived cytokines, eicosanoids products of arachidonic acid, and metabolites of estrogen and testosterone. Lifestyle factors that associate with more rapid progression of clinically early-stage prostate cancer are of increasing concern to health care providers and public health professionals. This research, to be completed over 5 years, will identify some of the biological reasons why obesity associates with more aggressive prostate cancer at diagnosis and decreases a man's chances for cure with surgery. It will also shed light on ways to prevent prostate cancer recurrence that may involve new or existing medicines or lifestyle changes.